A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.

Vaccination against hepatitis A and B in persons subject to homelessness in inner Sydney: vaccine acceptance, completion rates and immunogenicity.

OBJECTIVES: To determine acceptance, completion rates and immunogenicity of the standard vaccination schedule for hepatitis A (HAV) and B (HBV) in persons subject to homelessness. METHODS: A convenience sample of clients (n=201) attending a medical clinic for homeless and disadvantaged persons in Sydney was enrolled. Serological screening for HAV and HBV was undertaken. An appropriate vaccination program was instituted. Post-vaccination serology determined serological response. RESULTS: Although many clients had serological evidence of past infection, at least 138 (69%) clients had the potential to benefit from vaccination. For hepatitis A and B vaccinations, completion rates were 73% (73 of 100 clients) and 75% (69 of 92 clients), respectively; after vaccination, protective antibody was found in 98.2% (56 of 57) and 72% (36 of 50) of clients, respectively. CONCLUSION: A successful vaccination program can be mounted with a vulnerable population. We consider a clinic with a well-established history of acceptance and utilisation by the target group; a low staff turnover and regular clientele; inclusion of vaccination as part of routine client care; and counselling (part of pre- and post-serological testing) essential components in achieving good vaccination completion rates.

An audit of percutaneous endoscopic gastrostomy insertion in patients undergoing treatment for head and neck cancer: reducing the incidence of peri-operative airway events by the introduction of a tumour assessment protocol.

INTRODUCTION: The presence of a malignancy of the upper aerodigestive tract introduces the potential for iatrogenic complications additional to those usually associated with percutaneous endoscopic gastrostomy. Specifically, seeding of tumour from the upper aerodigestive tract creating abdominal wall metastases, and airway obstruction due to tumour directly occluding the airway when a patient is sedated for percutaneous endoscopic gastrostomy. PATIENTS AND METHODS: We report an audit of our experience of gastrostomy placement for patients under going treatment for head and neck cancer in our institution from September 2003 to October 2006. RESULTS: Of 33 patients who had percutaneous endoscopic gastrostomy insertion under sedation in the first cycle of the audit, two (6%) experienced major airway complications resulting in one fatality. A tumour assessment protocol was introduced. In the second cycle, 96 patients had percutaneous endoscopic gastrostomies, of whom 16 (13%) underwent gastrostomy insertion under general anaesthetic and five (4.5%) under radiological guidance. No patients had airway complications or abdominal wall metastases. CONCLUSIONS: A formal tumour assessment protocol eliminated airway obstruction as a complication of percutaneous endoscopic gastrostomy insertion and may reduce the potential for abdominal wall metastases at the gastrostomy site when using the pull technique.

Risk factors and seroprevalence of markers for hepatitis A, B and C in persons subject to homelessness in inner Sydney.

OBJECTIVE: To determine the seroprevalence of hepatitis A, B and C and the prevalence of risk factors for blood-borne infections in persons subject to homelessness attending a medical clinic in inner Sydney. METHOD: During 2003-05, 201 clients were enrolled in a prospective study to determine the acceptance, completion rates and immunogenicity of the standard vaccination schedule for hepatitis A and B. On enrolment, clients completed a risk factor assessment questionnaire and undertook pre-vaccination serological screening for hepatitis A, B and C. RESULTS: Forty-five per cent (85/188) of clients were positive for anti-HCV antibodies; 32% (60/189) showed evidence of past infection with HBV (anti-HBc); and 48% (89/189) were positive for anti-HAV antibodies. It was not uncommon for clients to have multiple markers of hepatitis. A past history of injecting drug use was significantly associated with markers for hepatitis B and C; age predicted presence of anti-HAV. A verbal history of infection appeared more reliable for hepatitis C, but considerably less so for hepatitis A and B. CONCLUSION: Persons subject to homelessness are at risk of blood-borne infection. The seroprevalence of markers for hepatitis B and C are higher than in the general population. IMPLICATIONS: Despite the high proportion of clients with serological markers for hepatitis A and B, at least 69% of clients could potentially benefit from hepatitis A and/or B vaccination.